Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples.
Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH "tag" SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case-control analyses (z = 2.99, P = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, P = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, P = 0.165), and combined analyses of all four samples were significant (rs1522305: chi(2) = 23.28, 8 d.f., P = 0.003). Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case-control results in African-Americans detected an association with L321L (P = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted.
Talkowski
Michael E
ME
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
McClain
Lora
L
Allen
Trina
T
Bradford
L Dianne
LD
Calkins
Monica
M
Edwards
Neil
N
Georgieva
Lyudmila
L
Go
Rodney
R
Gur
Ruben
R
Gur
Raquel
R
Kirov
George
G
Chowdari
Kodavali
K
Kwentus
Joseph
J
Lyons
Paul
P
Mansour
Hader
H
McEvoy
Joseph
J
O'Donovan
Michael C
MC
O'Jile
Judith
J
Owen
Michael J
MJ
Santos
Alberto
A
Savage
Robert
R
Toncheva
Draga
D
Vockley
Gerard
G
Wood
Joel
J
Devlin
Bernie
B
Nimgaonkar
Vishwajit L
VL
D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
D010651:Phenylalanine Hydroxylase